Suppression of long non‐coding RNA TNRC6C‐AS1 protects against thyroid carcinoma through DNA demethylation of STK4 via the Hippo signalling pathway

Abstract

Objectives: Thyroid carcinoma (TC) represents a malignant neoplasm affecting the thyroid. Current treatment strategies include the removal of part of the thyroid; however, this approach is associated with a significant risk of developing hypothyroidism.In order to adequately understand the expression profiles of TNRC6C-AS1 and STK4and their potential functions in TC, an investigation into their involvement with Hippo signalling pathway and the mechanism by which they influence TC apoptosis and autophagy were conducted.Methods: A microarray analysis was performed to screen differentially expressed lncRNAs associated with TC. TC cells were employed to evaluate the role of TNRC6C-AS1 by over-expression or silencing means. The interaction of TNRC6C-AS1 with methylation of STK4 promoter was evaluated to elucidate its ability to elicit autophagy, proliferation and apoptosis.Results: TNRC6C-AS1 was up-regulated while STK4 was down-regulated, where methylation level was elevated. STK4 was verified as a target gene of TNRC6C-AS1, which was enriched by methyltransferase. Methyltransferase's binding to STK4 increased expression of its promoter. Over-expressed TNRC6C-AS1 inhibited STK4 by promoting STK4 methylation and reducing the total protein levels of MST1 and LATS1/2. The phosphorylation of YAP1 phosphorylation was decreased, which resulted in the promotion of SW579 cell proliferation and tumorigenicity.Conclusion: Based on our observations, we subsequently confirmed the anti-proliferative, pro-apoptotic and pro-autophagy capabilities of TNRC6C-AS1 through STK4 methylation via the Hippo signalling pathway in TC.

The crosstalk between lncRNAs and the Hippo signalling pathway in cancer progression

“…For instance, YAP (or YAP1), a major transducer in downstream of Hippo pathway, is amplified and nuclear accumulated in a variety of cancers 19 . LncRNA TNRC6C antisense RNA 1 (TNRC6C‐AS1) was reported to be abundantly expressed in thyroid carcinoma and could regulate the subcellular localization and activation of YAP, leading to the promotion of cell proliferation and tumorigenicity 20 …”

Advances in Understanding the LncRNA-Mediated Regulation of the Hippo Pathway in Cancer

“…Mechanistically, MIR22HG was shown through bioinformatics analysis to be associated with the Hippo signaling pathway in thyroid cancer. Yang et al 69 demonstrated that overexpression of the lncRNA TNRC6C-AS1 promotes the proliferation of thyroid cancer cells while inhibiting their autophagy and apoptosis. A further investigation conducted by Peng et al 55 indicated that TNRC6C-AS1 is localized in the nucleus and that its overexpression significantly promotes the methylation of cytosine-phosphate-guanine (CpG) islands in the STK4 promoter region via the recruitment of methyltransferases, thus downregulating the expression of STK4.…”

LncRNA STK4 antisense RNA 1(STK4-AS1) affects the osteosarcoma cell cycle by regulating p53 protein

“…It is one of the antisense RNA of the STK4 gene. STK4 protein was reported to regulate many types of cancers, including liver cancer [34], prostate cancer [35], and thyroid carcinoma [36]. However, the effect of its antisense RNA was still unclear.…”